Process for preparing hexahydro-11 (eq)-CH2 CH2 COR5 -2,6-methano-3-benzazocines

ABSTRACT

Lower-alkyl 1-R 1  -3-R 5  CO-4aα-R 3  -5α-R 4  -6-R 2  &#34;-7-R 2  -8-R 2  &#39;-9-R 2  &#39;&#34;-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylates, useful as intermediates for the preparation of 3-R 1  -6(eq)-R 4  -7-R 2  &#34;-8-R 2  -9-R 2  &#39;-10-R 2  &#39;&#34;-11(ax)-R 3  -1,2,3,4,5,6,-hexahydro-11(eq)--CH 2  CH 2  COR 5  --2,6-methano-3-benzazocines, useful as analgesics and narcotic antagonists, are prepared by acylation of an appropriate lower-alkyl 1-R 1  -4aα-R 3  -5α-R 4  -6-R 2  &#34;-7-R 2  -8-R 2  &#39;-9-R 2  &#39;&#34;-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate or carboxylation of an appropriate 1-R 1  -3-COR 5  &#34;-4aα-R 3  -5α-R 4  -6-R 2  &#34;-7-R 2  -8-R 2  &#39;-9-R 2  &#39;&#34;-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline.

RELATED APPLICATIONS

This is a continuation-in-part of our prior, copending application Ser.No. 785,746, filed Apr. 8, 1977, now abandoned, which in turn is adivision of our prior, copending application Ser. No. 725,371, filedSept. 22, 1976, now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to lower-alkyl3-acyloctahydro-2,5-methanobenzo[g]quinoline-3-carboxylates, useful asintermediates for the preparation of1,2,3,4,5,6-hexahydro-11(eq)-(2-acylethyl)-2,6-methano-3-benzazocines,which in turn are useful as analgesics and analgesic antagonists.

(B) Description of the Prior Art

Sterling Drug Inc.-owned Japanese Pat. Appln. No. 60111/75, filed May20, 1975, published Dec. 25, 1975, under Provisional Patent PublicationNo. 160275 describes certain 3-acyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinolines useful asintermediates for the preparation of1,2,3,4,5,6-hexahydro-11(eq)-(2-acylethyl)-2,6-methano-3-benzazocines.Even under the most favorable reaction conditions, however, the priormethod produces, as a side product, substantial quantities of2-substituted-1,2,3,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines,thus appreciably diminishing the yield of the main product, thehexahydro-2,6-methano-3-benzazocines. Essentially identical disclosureto that in the above-indicated Japanese application is found in MichneU.S. Pat. No. 3,932,422, patented Jan. 13, 1976 on an application filedMay 20, 1974.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the present invention relates tocertain lower-alkyl 1-R₁ -3-R₅ CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂'-9-R₂'"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates,which are useful as intermediates for the preparation of certainhexahydro-2,6-methano-3-benzazocines.

In a process aspect, the invention relates to the process for thepreparation of certain 3-R₁ -6(eq)-R₄ -7-R₂ "-8-R₂ -9-R₂ '-10-R₂'"-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocines which comprises heating, with formic acid inan inert organic solvent or with a benzyl-di-lower-alkylammonium formateor a tri-lower-alkylammonium formate, certain lower-alkyl 1-R₁ -3-R₅CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂ '-9-R₂'"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, this invention provides valuable intermediates havingthe formula: ##STR1## and chemically designated lower-alkyl 1-R₁ -3-R₅CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂ '-9-R₂'"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates,which are useful in the preparation of 3-R₁ -6(eq)-R₄ -7-R₂ "-8-R₂ -9-R₂'-10-R₂ '"-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocines having the formula: ##STR2## where, in bothformulas I and II:

R₁ is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or3-furylmethyl, or such 2- or 3-furylmethyl substituted on theunsubstituted ring carbon atoms by from one to three methyl groups,phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ringby from one to two members of the group consisting of halogen (includingbromine, chlorine and fluorine), lower-alkyl, hydroxy,lower-alkyanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl,amino, lower-alkanoylamino or a single methylenedioxy attached toadjacent carbon atoms;

R₂, R₂ ', R₂ " and R₂ '" are each hydrogen, or three of them arehydrogen and the fourth is halogen (including bromine, chlorine orfluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy,lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino,lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groupstogether are methylenedioxy;

R₃ is hydrogen or lower-alkyl;

R₄ is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl,lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl,phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R₃and R₄ together are divalent lower-alkylene, --(CH₂)_(n) --, where n isone of the integers 3 or 4;

R₅ is lower-alkyl, lower-alkylthio-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH₂)_(m), where mis an integer from 2 to 4, or such 2- or 3-furyl or 2- or3-furyl-(CH₂)_(m) substituted on the unsubstituted ring carbon atoms byfrom one to three methyl groups, phenyl, phenyl-(CH₂)_(m), or phenyl orphenyl-(CH₂)_(m) substituted in the phenyl ring by from one or twomembers of the group consisting of halogen (including bromine, chlorineand fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy,lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or asingle methylenedioxy attached to adjacent carbon atoms; and

Alk is lower-alkyl.

As used herein, the terms lower-alkyl or lower-alkoxy mean saturated,acyclic groups which may be straight or branched containing from one toabout seven carbon atoms as exemplified by methyl, ethyl, propyl,isopropyl, butyl, nonadjacent t-butyl, methoxy, ethoxy, propoxy,isopropoxy or t-butoxy.

As used herein, the terms lower-alkenyl, halo-lower-alkenyl andlower-alkynyl represent monovalent groups of from three to seven carbonatoms containing one double or triple bond as illustrated, for example,by 1-propenyl, 2-butenyl, 4-pentenyl, 3-methyl-2-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-propynyl, 2-butynyl,4-pentynyl, 2-hexynyl and the like. The term halo-lower-alkenylincludes, for example, 3-chloro-2-propenyl, 3-bromo-2-propenyl,3,3-dichloro-2-propenyl, 3-bromo-2-methyl-2-propenyl and the like.

As used herein, the term cycloalkyl means saturated carbocyclic groupscontaining from three to seven ring carbon atoms as illustrated, forexample, by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-methylcyclobutyl, 4-ethylcyclohexyl and the like.

As used herein, the term lower-alkanoyl means such groups derived fromsaturated, aliphatic monocarboxylic acids having from one to four carbonatoms, as illustrated, for example, by formyl, acetyl, propionyl,butyryl, isobutyryl and the like.

The above-mentioned Japanese Provisional Patent Publication No. 160,275describes a process for preparing compounds of formula II whichcomprises heating a 1-R₁ -3-R₅ 'CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂'-9-R₂ '"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline offormula Ia below with formic acid in an inert organic solvent or with abenzyl-di-lower-alkylammonium formate or a tri-lower-alkylammoniumformate. The products of formula IIa are produced by ring opening of thestarting material of formula Ia by rupture of the bond indicated by theletter (b). The method however also produces, by rupture of the bondindicated by (a) followed by recyclization of the R₅ 'CO carbonyl groupto the nitrogen atom, significant amounts of 1-R₁ -2-R₅ '-4aα-R₃ -5α-R₄-6-R₂ "-7-R₂ -8-R₂'-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]-quinolines of formulaIII, thus diminishing the yield of the main product of formula IIa. Thetwo transformations are represented by the reaction sequence: ##STR3##where R₁, R₂, R₂ ', R₂ ", R₃ and R₄ have the meanings given above, andR₅ " is hydrogen, lower-alkyl, phenyl or phenyl-lower-alkyl.

According to the present invention, the compounds of formula II can beproduced in high yield, without the formation of side productsrepresented by formula III, by heating the novel β-keto esters offormula I with formic acid in an inert organic solvent or with abenzyl-di-lower-alkylammonium formate or a tri-lower-alkylammoniumformate at a temperature in the range from 120°-150° C. The reactionresults in simultaneous ring opening between the 2- and 3-ring carbonatoms of the compounds of formula I and hydrolysis and decarboxylationof the 3-carbo-lower-alkoxy group, COOAlk. Suitable solvents aretoluene, xylene or mesitylene. A preferred solvent medium is formic acidin mesitylene.

A further advantage of the use of the β-keto esters of formula I, ratherthan the compounds of formula Ia, is that use of the latter requires areaction time in the order of days, in some cases up to six days,whereas the β-keto esters of formula I usually require reaction times inthe order of minutes or hours, reaction in most cases being complete infour to six hours using formic acid in mesitylene as solvent or in nineto thirteen minutes using trimethylammonium formate at 145° C. In allcases, the course of the reaction is routinely followed by sampling thereaction mixture onto thin layer chromatography plates and noting thedisappearance, with increasing reaction time, of zones attributable tostarting material.

The compounds of formula I are prepared by either (A) reacting alower-alkyl 1-R₁ -4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂ '-9-R₂'"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateof formula Ib with an alkali metal amide, for example sodamide orlithium diisopropylamide, in an inert organic solvent and reacting thealkali metal salt thus formed with an appropriate acyl halide, R₅"-CO-X, or a lower-alkyl halo formate, X-COO-Alk, or (B) reacting a 1-R₁-3-R₅ "CO-4aα-R₃ -5α-R₄ -6-R₂ "-7-R₂ -8-R₂ '-9-R₂'"-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline offormula Ic with an alkali metal amide as in alternative (A) and reactingthe resulting alkali metal salt with a lower-alkyl halo formateaccording to the following reaction sequence: ##STR4## where R₁, R₂, R₂', R₂ ", R_(2'"), R₃, R₄ and Alk have the meanings given above, R₅ " hasthe same meanings as R₅ except it does not represent lower-alkoxy, X ishydrogen and M--N═B is an alkali metal (M) amide (N═B). The reaction ispreferably carried out at a temperature from about -10° C. to about -70°C. Suitable solvents are tetrahydrofuran, diethyl ether or dioxane.

The starting materials of formulas Ia, Ib and Ic and methods for theirpreparation are disclosed in U.S. Pat. No. 3,932,422.

As indicated above, the steric configurations of the3-carbo-lower-alkoxy group in the compounds of formula Ib, the 3-acylgroup (COR₅ ") in the compounds of formula Ic and of the 3-acyl (R₅ CO)and 3-carbo-lower-alkoxy groups (COOAlk) in the β-keto esters of formulaI are not known with absolute certainty. The esters of formula Ib andthe ketones of formulas Ia and Ic disclosed in Japanese ProvisionalPatent Publication No. 160,275 are disclosed herein as having theβ-configuration, i.e. the carbo-lower-alkoxy or the acyl group is cis tothe 2,5-methano bridge (vide infra). However, since the time ofpreparation and filing of the Japanese application, on which that patentpublication is based, some uncertainty has developed over whether theester or acyl groups have the α or the β-configuration. Insofar as thestructures of the hexahydro-2,6-methano-3-benzazocines of formula II(which are prepared from the β-keto esters of formula I) are concerned,the question of the steric configuration at the 3-position of thecompounds of formula I is moot, because the asymmetry at the 3-positionis destroyed on conversion of the compounds of formula I to thecompounds of formula II, and the compounds of formula I having bothpossible steric configurations at the 3-position are fully operable forthe preparation of the compounds of formula II. Suffice it to say thatacylation or carboxylation of the compounds of formula Ib orcarboxylation of the compounds of formula Ic followed by ring openingand decarboxylation gives, in each case, a single, clean product offormula II.

The compounds of this invention can exist in stereo-chemically isometricforms, that is, optical isomers and geometric isomers. If desired, theisolation or the production of a particular stereochemical form can beaccomplished by application of general principles known in the priorart. In the nomenclature employed for the compounds of formula II,herein, "ax" stands for axial and "eq" for equatorial, and theconfigurations are given with reference to the hydroaromatic ring. Thus,the 6(eq), 11(ax) compounds of formula II are in the cis configuration,whereas the 6(eq), 11(eq) compounds are in the trans configuration.

In the nomenclature employed for the compounds of formulas I, Ia, Ib, Icand III, again configurations are given with reference to thehydroaromatic ring, and the designation "β" indicates the cisconfiguration relative to the 2,5-methano bridge of the compounds offormula I or the 3,5-ethano bridge of the compounds of formula III.Conversely, the designation "α" indicates the trans configurationrelative to the same groups.

The structures of the compounds of this invention were established bythe modes of synthesis, by elementary analyses and by infrared andnuclear magnetic resonance spectra. The course of reactions andhomogeneity of the products were routinely ascertained by thin layerchromotography.

The manner and process of making and using the invention, and the bestmode contemplated of carrying out this invention, will now be describedso as to enable any person skilled in the art to which it pertains tomake and use the same. The melting points are uncorrected unless notedotherwise.

A. Preparation of Lower-alkyl 3-R₅-CO-Octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates of Formula I1- By acylation of the corresponding lower-alkyl 3-carboxylate Example 1

To a solution of 50 ml. (0.12 mole) of 2.4N n-butyl lithium in hexanewas added, over a period of about thirty minutes while maintaining thetemperature at 0° C., a solution of 13.1 g. (0.13 mole) of redistilleddiisopropylamine in 110 ml. of dry tetrahydrofuran. The mixture was thencooled to -60° C., and a solution of 34.3 g. (0.1 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein 110 ml. of tetrahydrofuran was added over a two hour period. Thesolution was then treated, over a period of about thirty minutes whilecooling at -60° C., with a solution of 18.8 g. (0.13 mole) ofredistilled hexanoyl chloride in 110 ml. of tetrahydrofuran. The clearreaction mixture was poured into 500 ml. of aqueous sodium bicarbonate,extracted with two 100 ml. portions of ether, and the combined etherextracts were washed once with brine and then dried over sodium sulfateand evaporated to dryness leaving 44 g. of an oil which solidified onstanding. The residue was recrystallized from hexane to give 27.5 g.(63%) of ethyl3-(1-oxohexyl)-7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate,m.p. 117°-120° C.

Following a procedure similar to that described in Example 1 above, thefollowing compounds of formula I were similarly prepared: A. Ethyl7-methoxy-1,4aα,5α-trimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate(22.8 g., 43%, m.p. 97°-100° C. from pentane) prepared by reaction of40.5 g. (0.12 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g[quinoline-3-carboxylatewith 0.13 mole of lithium diisopropylamide followed by reaction of theresulting salt with 17.5 g. (0.13 mole) of 4-methylpentanoyl chloride;B. Ethyl7-methoxy-1,5α-dimethyl-3-(1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate(5.2 g., 27%, m.p. 87°-92° C., from pentane) prepared by reaction of15.0 g. (0.046 mole) of ethyl7-methoxy-1,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatewith 0.047 mole of lithium diisopropylamide followed by reaction of theresulting salt with 5.7 g. (0.046 mole) of pentanoyl chloride.

Following a procedure similar to that described in Example 1 above, thefollowing compounds of formula I listed in Table 1 are similarlyprepared. The melting point and solvent used for crystallization aregiven in the column headed "m.p. (°C.)/Solv.".

                                      Table 1                                     __________________________________________________________________________                                        Alk/   m.p. (° C)/                 Example                                                                             R.sub.1 /R.sub.5                                                                         R.sub.2 /R.sub.2 "                                                                 R.sub.2 '/R.sub.2 "'                                                               R.sub.3 /R.sub.4                                                                       % Yield                                                                              Solv.                              __________________________________________________________________________    1C    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      109-111                                  (CH.sub.2).sub.2 CH.sub.3                                                                H    H    CH.sub.3 62     hexane                             1D    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      85-88                                    CH.sub.2 CH(CH.sub.3).sub.2                                                              H    H    CH.sub.3 44     hexane                             1E    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      113-115                                  CH.sub.2 CH.sub.3                                                                        H    H    CH.sub.3 53     hexane                             1F    CH.sub.3   CH.sub.3 O                                                                         H    H        C.sub.2 H.sub.5                                                                      120-123                                  CH.sub.3   H    H    CH.sub.3 28     ethanol                            1G    C.sub.3 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      90-92                                    (CH.sub.2).sub.3 CH.sub.3                                                                H    H    CH.sub.3 28     pentane                            1H    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub. 5                                                                     117.5-119                                (CH.sub.2).sub.3 SCH.sub.3                                                               H    H    CH.sub.3 59     hexane                             1J    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      120-122                                  CH.sub.3   H    H    CH.sub.3 40     benzene/hexane                     1K    CH.sub.3   CH.sub.3 O                                                                         H    H        C.sub.2 H.sub.5                                                                      106-108                                  (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3 39     ethanol                            1L    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      117-123                                  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         H    H    CH.sub.3 51     ethanol                            1M    C.sub.6 H.sub.5 CH.sub.2                                                                 H    H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3 78                                        1N    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      123-125                                  CH.sub.3   H    H    CH.sub.3 24     hexane                             1P    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      t-C.sub.4 H.sub.9                                                                        H    H    CH.sub.3 2                                         1Q    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3 65                                        1R    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.3 CH.sub.3                                                                H    H    CH.sub.3 37                                        1S    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.5 CH.sub.3                                                                H    H    CH.sub.3 80                                        1T    CH.sub.3   CH.sub.3                                                                           H    CH.sub.3 C.sub.2 H.sub.5                                                                      86-87                                    (CH.sub.2).sub.5 CH.sub.3                                                                H    H    CH.sub.3 7      ethanol                            1U    C.sub.3 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      89-91                                    (CH.sub.2).sub.3 CH.sub.3                                                                H    H    CH.sub.3 36     pentane                            1V    C.sub.6 H.sub.5 CH.sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                      H    H    CH.sub.3 46                                        1W    CH.sub.3   CH.sub.3 O                                                                         H    H        C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.5 CH.sub.3                                                                H    H    CH.sub.3 13                                        1X    CH.sub.3   CH.sub.3 O                                                                         H    H        C.sub.2 H.sub.5                                                                      oil                                      (CH.sub.2).sub.2 CH.sub.3                                                                H    H    CH.sub.3 64                                        1Y    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      oil                                      cyclopentyl(CH.sub.2).sub.2                                                              H    H    CH.sub.3 100+(crude)                               1Z    CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 Chd 2 H.sub.5                                                                        oil                                      cyclopropyl(CH.sub.2).sub.2                                                              H    H    Ch.sub.3 60                                        1AA   CH.sub.3   CH.sub.3 O                                                                         H    H        C.sub.2 H.sub.5                                                                      90.5-93.5                                (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                      H    H    CH.sub.3 62     ethanol                            1AB   CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      93.0-95.5                                (CH.sub.2).sub.3 CH.sub.3                                                                H    H    CH.sub.3 16     ethanol                            1AC   CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      142-144                                  2-furyl    H    H    CH.sub.3 26     acetone                            1AD   CH.sub.3   CH.sub.3 O                                                                         H    CH.sub.3 C.sub.2 H.sub.5                                                                      121-123                                  2-furyl-(CH.sub.2).sub.2                                                                 H    H    CH.sub.3 54     hexane                             1AE   CH.sub.3   H    H    H        C.sub.2 H.sub.5                                 cyclohexyl H    H    CH.sub.2 CH.sub.2 OCH.sub.3                        1AF   CH.sub.3   H    H    H        C.sub.2 H.sub.5                                 cyclohexyl-CH.sub.2                                                                      H    H    CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5                 1AG   C.sub.6 H.sub.5 CHhd 2                                                                   H    H    CH.sub.3 C.sub.2 H.sub.5                                 cyclopropyl                                                                              H    CH.sub.3 O                                                                         CH.sub.3                                           1AH   CH.sub.3   H    H    H        C.sub.2 H.sub.5                                 cyclopropyl-CH.sub.2                                                                     H    H    CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5                1AJ   CH.sub.3   H    H    H        C.sub.2 H.sub.5                                 C.sub.6 H.sub.5                                                                          H    H    CH=CH.sub.2                                        1AK   H          H    H    CH.sub.3 C.sub.2 H.sub.5                                 2-furyl-(CH.sub.2).sub.2                                                                 CH.sub.3 O                                                                         H    CH.sub.3                                           1AL   H          H    H    CH.sub.3 C.sub.2 H.sub.5                                 3-furyl-(CH.sub.2).sub.2                                                                 H    CH.sub.3 O                                                                         CH.sub.3                                           1AM   CH.sub.2 CH=CH.sub.2                                                                     H    H    CH.sub.3 C.sub.2 H.sub.5                                 5-CH.sub.3 -3-furyl-(CH.sub.2).sub.3                                                     H    H    CH.sub.3                                           1AN   CH.sub.2 CH=C(CH.sub.3).sub.2                                                            H    H    CH.sub.3 C.sub.2 H.sub.5                                 (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.2 CH.sub.2 OH                               1AP   CH.sub.2 C.tbd.CH                                                                        H    H    CH.sub.3 C.sub.2 H.sub.5                                 (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3                                           1AQ   C.sub.4 H.sub. 7 CH.sub.2                                                                H    H    CH.sub.3 C.sub.2 H.sub.5                                 (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3                                           1AR   3-furyl-CH.sub.2                                                                         H    H    CH.sub.3 C.sub.2 H.sub.5                                 (CH.sub.2).sub.4 CH.sub.3                                                                H    H    CH.sub.3                                           __________________________________________________________________________     2-By carboxylation of the corresponding 3-carboxylates or 3-R.sub.5 "CO       ketones                                                                  

EXAMPLE 2

A solution of 0.055 mole of lithium diisopropylamide in 60 ml. oftetrahydrofuran was prepared from butyl lithium and diisopropylamineusing the procedure described in Example 1 above. The solution thusprepared was cooled to -75° C. and treated with a solution of 17.1 g.(0.05 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateadded over a period of about thirty minutes while maintaining thetemperature at -75° C. The solution was then treated dropwise over aperiod of one hour at -75° C. with a solution of 5.4 g. (0.05 mole) ofethyl chloroformate in 80 ml. of tetrahydrofuran. The mixture wasstirred for one hour, then poured into 400 ml. of aqueous sodiumbicarbonate and worked up in the same manner as described in Example 1to give 9.7 g. of crude material which was recrystallized from pentaneto give 6.3 g. (30%) of diethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]uinoline-3,3-dicarboxylate,m.p. 89°-91° C.

Following a procedure similar to that described in Example 2, using anappropriate 3-R₅"CO-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline offormula Ic and ethyl chloroformate in the presence of diisopropylamide,the following compounds of formula I are similarly prepared.

                                      Table 2                                     __________________________________________________________________________    Example                                                                             R.sub.1 /R.sub.5                                                                           R.sub.2 /R.sub.2 "                                                                    R.sub.2 '/R.sub.2 "'                                                               R.sub.3 /R.sub.4                                                                      Alk                                   __________________________________________________________________________    2A    CH.sub.3     H        Cl  H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2B    CH.sub.3     H        Br  H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2C    CH.sub.3     H        F   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2D    CH.sub.3     H        CF.sub.3                                                                          H       Chd 2 H.sub.5                               CH.sub.3     H        H   CH.sub.3                                      2D    CH.sub.3     H        CF.sub.3                                                                          H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2E    CH.sub.3     H        CH.sub.3                                                                          H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2F    CH.sub.3     H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2G    CH.sub.3     H        H   CH.sub.3                                      2H    CH.sub.3     H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.2 CH.sub.2 Cl                          2J    CH.sub.3     H        H                                                                                  ##STR5##                                                                             C.sub.2 H.sub.5                             CH.sub.3     H        H                                                 2K    CH.sub.3     H        H                                                                                  ##STR6##                                           CH.sub.3     H        H                                                 2L    cyclohexyl   CH.sub.3 S                                                                             H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2M    4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 O                                                                             H   H       C.sub.2 H.sub.5- CH.sub.3 H H CH.s                                            ub.3                                  2N    4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 CONH                                                                          H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2P    4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       C.sub.2 H.sub.5 OCONH                                                                  H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2Q    4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                          H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2R    3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2S    3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                                            H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2T    4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H        H   C.sub.2 H.sub.5                                     CH.sub.3     H        H   CH.sub.3                                      2U    3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2V    3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                           H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2W                                                                                   ##STR7##    H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.3                                      2X    CH.sub.3     H        H   H       C.sub.2 H.sub.5                             CH.sub.3     H        H   CH.sub.2 CH.sub.2 SCH.sub.3                   2Y    CH.sub.3     H        H   H       C.sub.2 H.sub.5                             CH.sub.3     CH.sub.3 H   CH.sub.3                                      __________________________________________________________________________

b. conversion of the Compounds of Formula I to 1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ --COR₅ -2,6-methano-3-benzazocines of Formula II EXAMPLE 3

A solution of 10 g. (0.023 mole) of ethyl3-(1-oxohexyl)-7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein 475 ml. of mesitylene and 35 ml. of 97% formic acid was heated underreflux for seventeen and a half hours. The solvent was removed in vacuo,and the residue was treated with aqueous sodium bicarbonate and ether.The ether extracts were dried over anhydrous magnesium sulfate and thentreated with ethereal hydrogen chloride. The material which separatedwas collected and recrystallized from acetone to give two crops,totalling 6.5 g. (69%), of 8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinehydrochloride, m.p. 213°-215° C.

Following a procedure similar to that described in Example 3 above,using an appropriate lower-alkyl 3-R₅CO--1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateof formula I in refluxing mesitylene/97% formic acid, the following1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅ --2,6-methano-3-benzazocinesof formula II were similarly prepared. A.8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinehydrochloride (4.2 g., 38%, m.p. 228°-232° C. from acetone) prepared byrefluxing 12 g. (0.027 mole) of ethyl7-methoxy-1,4aα,5αtrimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein a solution of 500 ml. of mesitylene and 35 ml. of 97% formic acid fortwenty-one hours and isolating the product in the form of thehydrochloride salt.

Following a procedure similar to that described in Example 3 above thefollowing 1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocines of formula II were similarly prepared byheating an appropriate lower-alkyl 3--R₅CO--octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate in refluxingmesitylene/97% formic acid. The reaction time and % yield are given inthe last column. In each instance, R₂ ', R₂ " and R₂ '" are hydrogen,and unless noted otherwise, melting points are given for the free bases.

                                      Table 3                                     __________________________________________________________________________                                     Time (Hrs.)/                                 Example                                                                             R.sub.1 /R.sub.5                                                                        R.sub.2                                                                           R.sub.3 /R.sub.4                                                                  m.p.(° C.)/Solv.                                                                % Yield                                      __________________________________________________________________________    3B    CH.sub.3  CH.sub.3 O                                                                        H   182-185 (a)                                                                            24                                                 (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                          acetone  23                                           3C    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          98-99    22                                                 (CH.sub.2).sub.2 CH.sub.3                                                                   CH.sub.3                                                                          hexane   70                                           3D    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          95-97    24                                                 CH.sub.2 CH(CH.sub.3).sub.2                                                                 CH.sub.3                                                                          pentane  60                                           3E    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          100-103 (c)                                                                            24                                                 C.sub.2 H.sub.5                                                                             CH.sub.3                                                                          ethanol  63                                           3F    CH.sub.3  CH.sub.3 O                                                                        H   175-179 (b)                                                                            22                                                 CH.sub.3      CH.sub.3                                                                          acetone/ether                                                                          70                                           3G    C.sub.3 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          219-220 (b)                                                                            21                                                 (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          67                                           3H    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          163-165 (d)                                                                            24                                                 (CH.sub.2).sub.3 SCH.sub.3                                                                  CH.sub.3                                                                          acetone/ether                                                                          89                                           3J    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          176-179 (b)                                                                            13                                                 CH.sub.3      CH.sub.3                                                                          acetone/ether                                                                          58                                           3K    CH.sub.3  CH.sub.3 O                                                                        H   127.5-130 (e)                                                                          24                                                 (CH.sub.2).sub.4 CH.sub.3                                                                   CH.sub.3                                                                          ethanol  63                                           3L    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          176-179 (e)                                                                            17                                                 (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                            CH.sub.3                                                                          acetone  37                                           3M    C.sub.6 H.sub.5 CH.sub.2                                                                H   CH.sub.3                                                                          190-193 (b)                                                                            80                                                 (CH.sub.2).sub.4 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          39                                           3N    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          oil      20.5                                               CH.sub.3      CH.sub.3     56                                           3P    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          214-217 (b)                                                                            6.75                                               (CH.sub.2).sub.4 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          28                                           3Q    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          226-228 (b)                                                                            21                                                 (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          88                                           3R    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          219-221 (b)                                                                            28                                                 (CH.sub.2).sub.5 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          69                                           3S    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          178-182 (b)                                                                            20                                                 (CH.sub.2).sub.5 CH.sub.3                                                                   CH.sub.3                                                                          ether    84                                           3T    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                        CH.sub.3                                                                          221-225° C. (b)                                                                 24                                                 (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         CH.sub.3                                                                          acetone/ether                                                                          36                                           3U    CH.sub.3  CH.sub.3 O                                                                        H   oil      24                                                 (CH.sub.2).sub.2 CH.sub.3                                                                   CH.sub.3     67                                           3V    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          220-222 (b)                                                                            15                                                 cyclopentyl(CH.sub.2).sub.2                                                                 CH.sub.3                                                                          ethanol/ether                                                                          48                                           3W    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          224-225 (b)                                                                            24                                                 cyclopropyl(CH.sub.2).sub.2                                                                 CH.sub.3                                                                          ethanol/ether                                                                          20                                           3X    CH.sub.3  CH.sub.3 O                                                                        H   131-135 (c)                                                                            16                                                 (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                         CH.sub.3                                                                          methanol 5                                            3Y    CH.sub.3  CH.sub.3 O                                                                        CH.sub.3                                                                          209-212 (b)                                                                            21                                                 (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                          acetone/ether                                                                          46                                           __________________________________________________________________________     (a) Picrate salt                                                              (b) Hydrochloride salt                                                        (c) Methanesulfonate melts 215-220                                            (d) Methanesulfonate salt                                                     (e) p-Toluenesulfonate salt                                              

EXAMPLE 4

To a solution of 30 ml. of trimethylammonium formate (prepared byaddition of two parts of trimethylamine to five parts of 97% formicacid) heated to 100° C. was added 8.3 g. (0.02 mole) of diethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3,3-dicarboxylate(described above in Example 2), and the mixture was heated to boilingfor fifteen minutes. The mixture was then poured onto ice, basified withexcess sodium hydroxide and extracted with ether. The ether extractswere washed once with brine, dried over magnesium sulfate and taken todryness to give 6.5 g. of a colorless oil which was recrystallized fromhexane to give 3.8 g. (55%) of ethyl3-[8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin11(eq)-yl]propionate,m.p. 91°-93° C.

Following a procedure similar to that described in Example 4 above,using an appropriate lower-alkyl 3--R₅CO--1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateof formula I in trimethylammonium formate, the following1,2,3,4,5,6-hexahydro-11(eq)--CH₂ CH₂ COR₅ -2,6-methano-3-benzazocinesof formula II were similarly prepared. A.8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-[3-oxo3-(2-furyl)propyl]-2,6-methano-3-benzazocine(1.5 g., 10%, m.p. 119°--122° C. from acetone) prepared by heating 20.5g. (0.04 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-3-(2furoyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylatein 60 ml. of a solution of trimethylammonium formate to boiling fortwelve minutes and isolating the product in the form of the free base.B.8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-[3-oxo-5-(2-furyl)pentyl]-2,6-methano-3-benzazocine(0.600 g., 71%, m.p. 144°-149° C. from acetone/ether) prepared byheating 1.0 g. (0.0022 mole) of ethyl 7-methoxy-1,4a,α,5α-trimethyl-3-[3-(2-furyl)-1-oxopropyl]1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein 10 ml. of a solution of trimethylammonium formate to boiling for tenminutes and isolating the product in the form of the free base.

EXAMPLES 5A-5AT

Following a procedure similar to that described in Example 3 using anappropriate lower-alkyl 3-R₅CO-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate of formula I,the following 1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅-2,6-methano-3-benzazocines of formula II are prepared.

                                      Table 5                                     __________________________________________________________________________    Example                                                                             R.sub.1 /R.sub.5                                                                           R.sub.2 /R.sub.2 "                                                                    R.sub.2 '/R.sub.2 '"                                                               R.sub.3 /R.sub.4                              __________________________________________________________________________    5A    C.sub.6 H.sub.5 CH.sub.2                                                                   CH.sub.3 O                                                                            H    CH.sub.3                                            t-C.sub.4 H.sub.9                                                                          H       H    CH.sub.3                                      5B    C.sub.3 H.sub.5 CH.sub.2                                                                   CH.sub.3 O                                                                            H    CH.sub.3                                            (CH.sub.2).sub.3 CH.sub.3                                                                  H       H    CH.sub.3                                      5C    CH.sub.3     CH.sub.3 O                                                                            H    H                                                   (CH.sub.2).sub.5 CH.sub.3                                                                  H       H    CH.sub.3                                      5D    CH.sub.3     H       H    H                                                   cyclohexyl   H       H    CH.sub.2 CH.sub.2 OCH.sub.3                   5E    CH.sub.3     H       H    H                                                   cyclohexyl-CH.sub.2                                                                        H       H    C.sub.2 CH.sub.2 SC.sub.6 H.sub.5             5F    C.sub.6 H.sub.6 CH.sub.2                                                                   H       H    CH.sub.3                                            cyclopropyl  H       CH.sub.3 O                                                                         CH.sub.3                                      5G    CH.sub.3     H       H    H                                                   cyclopropyl-CH.sub.2                                                                       H       H    CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5           5H    CH.sub.3     H       H    H                                                   C.sub.6 H.sub.5                                                                            H       H    CHCH.sub.2                                    5J    H            H       H    CH.sub.3                                            2-furyl-(CH.sub.2 ).sub.2                                                                  CH.sub.3 O                                                                            H    CH.sub.3                                      5K    H            H       H    CH.sub.3                                            3-furyl-(CH.sub.2).sub.2                                                                   H       CH.sub.3 O                                                                         CH.sub.3                                      5L    CH.sub.2 CHCH.sub.2                                                                        H       H    CH.sub.3                                            5-CH.sub.3 -3-furyl-(CH.sub.2).sub.3                                                       H       H    CH.sub.3                                      5M    CH.sub.2 CHC(CH.sub.3).sub.2                                                               H       H    CH.sub.3                                            (CH.sub.2).sub.4 CH.sub.3                                                                  H       H    CH.sub.2 CH.sub.2 OH                          5N    CH.sub.2 CCH H       H    CH.sub.3                                            (CH.sub.2).sub.4 CH.sub.3                                                                  H       H    CH.sub.3                                      5P    C.sub.4 H.sub.7 CH.sub.2                                                                   H       H    CH.sub.3                                            (CH.sub.2).sub.4 CH.sub.3                                                                  H       H    CH.sub.3                                      5Q    3-furyl-CH.sub.2                                                                           H       H    CH.sub.3                                            (CH.sub.2).sub.4 CH.sub.3                                                                  H       H    CH.sub.3                                      5R    CH.sub.3     H       Cl   H                                                   CH.sub.3     H       H    CH.sub.3                                      5S    CH.sub.3     H       Br   H                                                   CH.sub.3     H       H    CH.sub.3                                      5T    CH.sub.3     H       F    H                                                   CH.sub.3     H       H    CH.sub.3                                      5U    CH.sub.3     H       CF.sub.3                                                                           H                                                   CH.sub.3     H       H    CH.sub.3                                      5V    CH.sub.3     H       CH.sub.3                                                                           H                                                   CH.sub.3     H       H    CH.sub.3                                      5W    CH.sub.3     C.sub.6 H.sub.5                                                                       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5X    CH.sub.3     OCH.sub.2 O  H                                                   CH.sub.3     H       H    CH.sub.3                                      5Y    CH.sub.3     H       H    H                                                   CH.sub.3     H       H    CH.sub.2 CH.sub.2 Cl                          5Z    CH.sub.3     H       H                                                                                   ##STR8##                                           CH.sub.3     H       H                                                  5AA   CH.sub.3     H       H                                                                                   ##STR9##                                           CH.sub.3     H       H                                                  5AB   cyclohexyl   CH.sub.3 S                                                                            H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AC   4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 O                                                                            H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AD   4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                      CH.sub.3 CONH                                                                         H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AE   4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       C.sub.2 H.sub.5 OCONH                                                                 H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AF   4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                          H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AG   3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AH   3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                   H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AJ   4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AK   3-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AL   3-CH.sub.3 CONHC.sub.6 H.sub.6 CH.sub.2 CH.sub.2                                           H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AM                                                                                  ##STR10##   H       H    H                                                   CH.sub.3     H       H    CH.sub.3                                      5AN   CH.sub.3     H       H    H                                                   CH.sub.3     H       H    CH.sub.2 CH.sub.2 SCH.sub.3                   5AP   CH.sub.3     H       H    H                                                   CH.sub.3     CH.sub.3                                                                              H    CH.sub.3                                      __________________________________________________________________________

c. comparison of Claimed and Prior Methods

The superior overall yield obtained in the instant process for thepreparation of 3-benzazocines of formula II in comparison with theprocess of the prior method disclosed in Japanese Provisional PatentPublication No. 160,275 (and U.S. Pat. No. 3,932,422) is demonstrated bythe following descriptions which compare the stepwise and overall yieldsobtained in the preparation of8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinevia the instant process through the intermediate ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylateof formula I and via the prior art process through the intermediate7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylicacid and7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolineof formula Ic (R₅ " is CH₃) from a common starting material, ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate,of formula Ib. The procedures are illustrated by the reaction sequences:##STR11##

A. The Claimed Process

(Step 1A) A solution of 0.127 mole of lithium diisopropylamide in 150ml. of tetrahydrofuran was prepared using the procedure described abovein Example 1. The solution thus prepared was cooled to -70° C. andtreated over a period of two hours with stirring with a solution of 40.4g. (0.118 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein 200 ml. of tetrahydrofuran. When addition was complete, the mixturewas stirred for an additional thirty minutes and then treated withstirring over a period of one hour with a solution of 9.9 g. (0.127mole) of acetyl chloride in 150 ml. of tetrahydrofuran while maintainingthe temperature at -70° C. The reaction mixture was then worked up inthe manner described above in Example 1, and the crude productrecrystallized from hexane to give 18.2 g. (40%) of ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate,m.p. 120°-123° C.

(Step 2A) A solution of 1.23 g. (0.0032 mole) of the latter in 22 ml. ofmesitylene and 81.8 ml. of 97% formic acid was heated under reflux fornineteen hours and then worked up in the manner described above inExample 3. The product was isolated in the form of the free base to give0.36 g. (36%) of8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine,m.p. 67-69° C. (14% overall yield from the original starting material).

B. The Prior Process

(Step 1B) A solution of 10.0 g. (0.029 mole) of ethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylatein 100 ml. of ethanol and 50 ml. of water containing 2 g. (0.05 mole) ofsodium hydroxide was heated under reflux for about sixteen hours andthen concentrated to a small volume. The residue was diluted with about20 ml. of water, and the pH was adjusted to about 6.5-7.0 with dilutehydrochloric acid. The mixture was diluted with 200 ml. of ethanol,filtered, and the filtrate taken to dryness in vacuo. After drying theresidue by repeated concentration from boiling benzene and toluene, theproduct was crystallized from acetonitrile to give 7.9 g. (>100%) of7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylicacid, m.p. 118°-121° C.

(Step 2B) A solution of 3.15 g (0.010 mole) of the latter in 50 ml. ofanhydrous tetrahydrofuran was treated dropwise with stirring under anitrogen atmosphere with 20 ml. (0.020 mole) of a 1.7 molar solution ofmethyl lithium. The mixture was stirred for about thirty minutes andthen poured into a solution containing 10 g. of ammonium chloride in 100ml. of water. The mixture was extracted twice with ether, the etherextracts dried over magnesium sulfate and taken to dryness to give 1.4g. of a brown oil which was extracted with boiling pentane to give 0.5g. (16%) of7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline.The aqueous layer remaining after extraction of the crude product withether was saturated with solid sodium hydroxide, and the oil whichseparated was dissolved in water, acidified strongly and the solid whichseparated was collected, dried and converted to the hydrochloride saltto give 2.2 g. (0.0062 mole) of the hydrochloride salt (m.p. 295°-297°C.) of the starting carboxylic acid. The corrected yield for thereaction based on the recovered starting material is thus 42%.

(Step 3B) A solution of 1.0 g. (0.0032 mole) of the7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolineobtained in step 2 above was heated in a solution of 22 ml. ofmesitylene and 1.8 ml. of formic acid for a total of sixty-seven hours,the course of the reaction being followed from time to time by thinlayer chromatography. The reaction mixture was worked up in the mannerdescribed above in Example 3 to give 60 mg. (6%) of8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine,m.p. 62°-65° C. The overall yield from the original starting materialwas 2.5% based on recovered starting material in step 2.

We claim:
 1. The process for preparing a compound having the formula##STR12## where: R₁ is hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl,2- or 3-furylmethyl, or such 2- or 3-furylmethyl substituted on theunsubstituted ring carbon atoms by from one to three methyl groups,phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ringby from one to two members of the group consisting of halogen,lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy,lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or asingle methylenedioxy attached to adjacent carbon atoms;R₂, r₂ ', r₂ "and R₂ '" are each hydrogen, or three of them are hydrogen and thefourth is halogen, lower-alkyl, hydroxy, lower-alkanoyloxy,lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino,lower-alkanoylamino, lower-alkoxy-carbonylamino or phenyl, or two of theadjacent such groups together are methylenedioxy; R₃ is hydrogen orlower-alkyl; R₄ is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl,lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl,phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R₃ andR₄ together are divalent lower-alkylene, --(CH₂)_(n) --, where n is oneof the integers 3 or 4; R₅ is lower-alkyl, lower-alkylthio-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl,cycloalkyl-lower-alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH₂)_(m), where mis an integer from 2 to 4, or such 2- or 3-furyl or 2- or3-furyl-(CH₂)_(m) substituted on the unsubstituted ring carbon atoms byfrom one to three methyl groups, phenyl, phenyl-(CH₂)_(m), or phenyl orphenyl-(CH₂)_(m) substituted in the phenyl ring by from one to twomembers of the group consisting of halogen, lower-alkyl, hydroxy,lower-alkanoyloxy, lower-alkoxy, lower-alkyl-mercapto, trifluoromethyl,amino, lower-alkanoylamino or a single methylenedioxy attached toadjacent carbon atoms which comprises heating, with formic acid in aninert organic solvent or with a benzyl-di-lower-alkylammonium formate ora tri-lower-alkylammonium formate, a compound having the formula##STR13## where R₁, R₂, R₂ ', R₂ ", R₂ '", R₃, R₄ and R₅ have themeanings given above, and Alk is lower-alkyl.
 2. A process according toclaim 1 where R₁ is lower-alkyl or cycloalkyl-lower-alkyl; R₂ islower-alkoxy; R₂ ', R₂ " and R₂ '" are each hydrogen; and R₄ islower-alkyl.
 3. A process for preparing a compound according to claim 2where R₅ is lower-alkyl.
 4. A process for preparing a compound accordingto claim 2 where R₅ is lower-alkylthio-lower-alkyl.
 5. A process forpreparing a compound according to claim 2 where R₅ is phenyl-(CH₂)_(m).6. A process for preparing a compound according to claim 2 where R₅ islower-alkoxy.
 7. A process for preparing a compound according to claim 2where R₅ is 2-furyl.
 8. A process for preparing a compound according toclaim 2 where R₅ is 2-furyl-lower-alkyl.
 9. The process according toclaim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxohexyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.10. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.11. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxohexyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxobutyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.12. The process according to claim 3 for preparing8-methoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,5α-dimethyl-3-(1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.13. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-5-methylhexyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(3-methyl-1-oxobutyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.14. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxopentyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxopropyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.15. The process according to claim 3 for preparing8-methoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,5α-dimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.16. The process according to claim 3 for preparing8-methoxy-3-cyclopropylmethyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocinefrom ethyl1-cyclopropylmethyl-7-methoxy-4aα,5α-dimethyl-3-(1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate.17. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.18. The process according to claim 3 for preparing8-methoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,5α-dimethyl-3-(1-oxohexyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.19. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxononyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoheptyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.20. The process according to claim 3 for preparing8-methoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-6-methylheptyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,5α-dimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.21. The process according to claim 3 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxopentyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.22. The process according to claim 4 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-[(6-methylthio)-3-oxohexyl]-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-[(4-methylthio)-1-oxobutyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate.23. The process according to claim 5 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6,-hexahydro-11(eq)-(3-oxo-5-phenylpentyl)-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-(1-oxo-3-phenylpropyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.24. The process according to claim 6 for preparing ethylβ-{3-[8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-11(eq)-yl]}propionatefrom diethyl7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3,3-dicarboxylate.25. The process according to claim 7 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-[3-oxo-3-(2-furyl)propyl]-2,6-methano-3-benzazocinefrom ethyl 7-methoxy-1,4aα,5α-trimethyl-3-(2-furoyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.26. The process according to claim 8 for preparing8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-[3-oxo-5-(2-furyl)pentyl]-2,6-methano-3-benzazocinefrom ethyl7-methoxy-1,4aα,5α-trimethyl-3-[3-(2-furyl)-1-oxopropyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate.